There is a well-known link between cancer and inflammation. Chronic inflammatory diseases are known to increase risk for developing tumors, and tumors provoke multiple inflammatory responses in order to avoid immune system detection and destruction (Pardoll, 2012; Grivennikov et al., 2010). Cancers are able to exploit regulatory immune system mechanisms, promoting angiogenesis, immunosuppression, and metastasis (Du et al., 2008; Lin et al., 2006; Bronte et al., 2000; Bunt et al., 2006; Kim et al., 2009). These regulatory mechanisms include the activation of myeloid-derived suppressor cells (MDSCs) and immune checkpoint pathways (Korman et al., 2006; Nagaraj et al., 2013; Talmadge and Gabrilovich, 2013).
The disruption of immune checkpoints including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) using antibodies to these receptors has shown promising responses in a subset of patients in recent clinical trials (Nodi et al., 2010; Topalian et al., 2012; Brahmer et al., 2012; Wolchok et al., 2013). However, the majority of patients and tumor types in these trials remain unresponsive to this immunotherapy. A study by Kim et al. (2014) indicated that elevated levels of MDSCs may interfere with checkpoint inhibitor treatment by directly inhibiting the function of CD8+ T cells. Previously it was reported that blocking the PI3-kinase (PI3K) isoform p110γ can inhibit tumor inflammation, growth and metastasis by suppressing MDSCs in a model of spontaneous breast cancer (Schmid, 2011).
One report provides evidence of synergy between a pan-PI3K inhibitor and immune checkpoint blockers to PD1/CTLA4 (Kim et al., 2014). That report demonstrated that reduction in MDSCs via PI3K inhibition contributes to synergy with checkpoint blockade in syngeneic mouse breast and colon tumor models. Pan-PI3K inhibitors have been recently tested in clinical trials, but they broadly inhibit all PI3K isorforms and have been shown to have many deleterious side effects (Cleary and Shapiro, 2010).
In view of the foregoing, there is a need for the development of new and better compositions for reducing MDSCs during immune checkpoint blockade. The present invention is directing to meeting these and other needs.